2 research outputs found
Drug Resistance: The Role of Exosomal miRNA in the Microenvironment of Hematopoietic Tumors
Extracellular vesicles (EVs), including exosomes, have an important role thanks to their ability to communicate and exchange information between tumor cells and the tumor microenvironment (TME), and have also been associated with communicating anti-cancer drug resistance (DR). The increase in proliferation of cancer cells alters oxygen levels, which causes hypoxia and results in a release of exosomes by the cancer cells. In this review, the results of studies examining the role of exosomal miRNA in DR, and their mechanism, are discussed in detail in hematological tumors: leukemia, lymphoma, and multiple myeloma. In conclusion, we underline the exosome’s function as a possible drug delivery vehicle by understanding its cargo. Engineered exosomes can be used to be more specific for personalized therapy
LINKING ENDOPLASMIC RETICULUM STRESS TO NEURODEVELOPMENTAL DISORDERS
Autism spectrum disorders are a group of neurodevelopmental
disorders with a strong genetic background. One of the most
characterized autism-linked mutations is the R451C substitution
in the synaptic protein Neuroligin3 (NLGN3). The mutation
induces a local misfolding in the extracellular domain causing
the retention of NLGN3 in the Endoplasmic Reticulum (ER)1.
The presence of misfolded protein in the ER can lead to the activation
of the Unfolded Protein Response (UPR), implicated in
several neurological diseases and in the regulation of neurotransmission
and plasticity2. Our aim is to ascertain whether the
ER retention of the R451C NLGN3 mutant protein activates
the UPR. We have generated a new PC12 Tet-On model system
with inducible expression of NLGN3, either wild type or R451C
proteins, for studying the UPR signaling in time-course experiments.
PC12 clones were characterized for NLGN3 expression,
by western blots and immunofluorescence. Wild type NLGN3
protein is correctly trafficked to the cell surface, with the
R451C NLGN3 being retained in the ER, as shown by sensitivity
to endoglycosidase H. Our results indicate that PC12 clones
expressing the R451C mutant NLGN3, activate all UPR signaling
pathways downstream of the ATF6, IRE1 and PERK stress
sensors. Synthesis of R451C NLGN3 induces the up-regulation
of UPR target genes, such as BiP and CHOP, before and after
differentiating the cells to a neuronal phenotype. In order to
understand the potential role of UPR in neurodevelopmental
disorders, we are currently investigating its activation in the
Knock In mouse model of autism, carrying the R451C mutation
in the NLGN3 endogenous gene. Our data represent the first evidence
on the effects of the R451C NLGN3 in activating the
UPR and represent a solid link between UPR and neurodevelopmental
disorders characterized by the retention of misfolded
proteins in the ER